Therapeutic substituted lactams

ABSTRACT

Disclosed herein are compounds having a formula: (I) Compositions, methods, and medicaments related thereto are also disclosed.

CROSS-REFERENCE

This is a national stage application under 35 U.S.C. §371 of PCT patentapplication PCT/US08/80063, filed on Oct. 16, 2008, which claims thebenefit of U.S. Provisional Application Ser. No. 60/981,918, filed Oct.23, 2007 and U.S. Application Ser. No. 60/984,838, filed Nov. 2, 2007,each of which is hereby incorporated by reference in its entirety.

DESCRIPTION OF THE INVENTION

Disclosed herein are compounds having a formula:

wherein Y has from 0 to 14 carbon atoms and is: an organic acidfunctional group, or an amide or ester thereof; hydroxymethyl or anether thereof; or a tetrazolyl functional group;

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene, the sum of m    and o is 1, 2, 3, or 4, and wherein 1 —CH₂— may be replaced by S or    O, and 1 —CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—;-   G and G′ are independently —H, —OH, —O-alkyl having from 1 to 6    carbon atoms, halo, C₁₋₆ alkyl, —CF₃, —CN, or ═O; and-   B is aryl.

These compounds are useful for reducing intraocular pressure. Reductionof intraocular pressure has been shown to delay or prevent the onset ofprimary open angle glaucoma, and to delay or prevent further vision lossin patients with primary open angle glaucoma. Thus, these compounds arealso useful for treating glaucoma. Different types of suitable dosageforms and medicaments are well known in the art, and can be readilyadapted for delivery of the compounds disclosed herein. For example, thecompound could be dissolved or suspended in an aqueous solution oremulsion that is buffered to an appropriate pH, and administeredtopically to an eye of a mammal.

For the purposes of this disclosure, “treat,” “treating,” or “treatment”refer to the use of a compound, composition, therapeutically activeagent, or drug in the diagnosis, cure, mitigation, treatment, orprevention of disease or other undesirable condition.

Stable means that a compound is sufficiently stable to be stored in abottle at room temperature under a normal atmosphere for at least 12hours, or stable enough to be useful for any purpose disclosed herein.

Unless otherwise indicated, reference to a compound should be construedbroadly to include pharmaceutically acceptable salts, prodrugs,tautomers, alternate solid forms, non-covalent complexes, andcombinations thereof, of a chemical entity of a depicted structure orchemical name.

A pharmaceutically acceptable salt is any salt of the parent compoundthat is suitable for administration to an animal or human. Apharmaceutically acceptable salt also refers to any salt which may formin vivo as a result of administration of an acid, another salt, or aprodrug which is converted into an acid or salt. A salt comprises one ormore ionic forms of the compound, such as a conjugate acid or base,associated with one or more corresponding counter-ions. Salts can formfrom or incorporate one or more deprotonated acidic groups (e.g.carboxylic acids), one or more protonated basic groups (e.g. amines), orboth (e.g. zwitterions).

A prodrug is a compound which is converted to a therapeutically activecompound after administration. For example, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Prodrug preparation is well known in the art. For example, “Prodrugs andDrug Delivery Systems,” which is a chapter in Richard B. Silverman,Organic Chemistry of Drug Design and Drug Action, 2d Ed., ElsevierAcademic Press: Amsterdam, 2004, pp. 496-557, provides further detail onthe subject. In particular, alkyl esters having such as methyl, ethyl,isopropyl, and the like are contemplated. Also contemplated are prodrugscontaining a polar group such as hydroxyl or morpholine. Examples ofsuch prodrugs include compounds containing the moieties —CO₂(CH₂)₂OH,

and the like.

Tautomers are isomers that are in rapid equilibrium with one another.For example, tautomers may be related by transfer of a proton, hydrogenatom, or hydride ion.

Unless stereochemistry is explicitly and unambiguously depicted, astructure is intended to include every possible stereoisomer, both pureor in any possible mixture.

Alternate solid forms are different solid forms than those that mayresult from practicing the procedures described herein. For example,alternate solid forms may be polymorphs, different kinds of amorphoussolid forms, glasses, and the like.

Non-covalent complexes are complexes that may form between the compoundand one or more additional chemical species that do not involve acovalent bonding interaction between the compound and the additionalchemical species. They may or may not have a specific ratio between thecompound and the additional chemical species. Examples might includesolvates, hydrates, charge transfer complexes, and the like.

Y is an organic acid functional group, or an amide or ester thereof; orY is hydroxymethyl or an ether thereof; or Y is a tetrazolyl functionalgroup. For the purposes of this disclosure, Y is limited to from 0 to 14carbon atoms, from 0 to 5 oxygen atoms, from 0 to 2 nitrogen atoms, from0 to 2 sulfur atoms, and from 0 to 1 phosphorous, and any necessaryhydrogen atoms.

An organic acid functional group is an acidic functional group on anorganic molecule. While not intending to be limiting, organic acidfunctional groups may comprise an oxide of carbon, sulfur, orphosphorous. Thus, while not intending to limit the scope of theinvention in any way, in certain compounds Y is a carboxylic acid,sulfonic acid, or phosphonic acid functional group.

Esters and amides of organic functional groups are carbonyl groupsdirectly attached to a nitrogen or oxygen atom. Thus, esters of amidesof carboxylic acids, sulfonic acid, and

Acids Esters Amides

An amide may also have an —SO₂— moiety. For example the amide—CONHSO₂R³, wherein R³ is a hydrocarbyl of from 1 to 14 carbon atoms, iscontemplated. R, R¹, R², and R³ are hydrocarbyl subject to theconstraint that Y may not have more than 14 carbon atoms.

Hydrocarbyl is a moiety consisting of carbon and hydrogen, including,but not limited to:

-   -   a. alkyl, which is hydrocarbyl that contains no double or triple        bonds, such as:        -   linear alkyl, e.g. methyl, ethyl, n-propyl, n-butyl,            n-pentyl, n-hexyl, etc.,        -   branched alkyl, e.g. iso-propyl, t-butyl and other branched            butyl isomers, branched pentyl isomers, etc.,        -   cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,            cyclohexyl, etc.,        -   combinations of linear, branched, and/or cycloalkyl;    -   b. alkenyl, which is hydrocarbyl having 1 or more double bonds,        including linear, branched, or cycloalkenyl    -   c. alkynyl, which is hydrocarbyl having 1 or more triple bonds,        including linear, branched, or cycloalkynyl;    -   d. combinations of alkyl, alkenyl, and/or akynyl

C₁₋₆ hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

C₁₋₆ alkyl is alkyl having 1, 2, 3, 4, 5, or 6, carbon atoms such asmethyl, ethyl, propyl isomers, butyl isomers, pentyl isomer, and hexylisomers, etc.

Hydroxyalkyl is alkyl-OH, such as hydroxymethyl, hydroxyethyl, etc. C1-6hydroxyalkyl is hydroxyalkyl having 1, 2, 3, 4, 5, or 6, carbon atoms.

An ether of hydroxymethyl is —CH₂OR.

An unsubstituted tetrazolyl functional group has two tautomeric forms,which can rapidly interconvert in aqueous or biological media, and arethus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, unsubstituted and hydrocarbyl substituted tetrazolyl upto C₁₄ are considered to be within the scope of the term “tetrazolyl.”

In one embodiment, Y is —CO₂R⁴, —CONR⁵R⁶, —CON(CH₂CH₂OH)₂,—CONH(CH₂CH₂OH), —CH₂OH, —P(O)(OH)₂, —CONHSO₂R⁴, —SO₂NR⁵R⁶,

wherein R⁴, R⁵ and R⁶ are independently H, C₁-C₆ alkyl, C₁₋₆hydroxyalkyl, unsubstituted phenyl, or unsubstituted biphenyl, providedthat Y has no more than 14 carbon atoms.

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene, the sum of m and o is 1, 2, 3, or 4, andwherein 1 —CH₂— may be replaced by S or O, and 1 —CH₂—CH₂— may bereplaced by —CH═CH— or —C≡C—(CH₂)₃—.

Thus, A may be —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S or O. For example, A maybe a moiety where S replaces one or two carbon atoms such as one of thefollowing or the like.

Alternatively, A may be a moiety where 0 replaces one or two carbonatoms such as one of the following or the like.

Alternatively, A may have an O replacing one carbon atom and an Sreplacing another carbon atom, such as one of the following or the like.

Alternatively, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or, the sum of m and o is 1, 2, 3, or 4, andwherein 1 —CH₂— may be replaced by S or O, and 1 —CH₂—CH₂— may bereplaced by —CH═CH— or —C≡C—. In other words,

in one embodiment A comprises:

-   -   1) a) 1, 2, 3, or 4 —CH₂— moieties, or        -   b) 0, 1 or 2 —CH₂— moieties and —CH═CH— or —C≡C—; and    -   2) Ar;    -   e.g. —CH₂—Ar—, —(CH₂)₂—Ar—, —CH═CH—Ar—, —C≡C—Ar—, —CH₂—Ar—CH₂—,        —CH₂Ar—(CH₂)₂—, —CH₂Ar—CH═CH—, —CH₂Ar—C≡C—, —(CH₂)₂—Ar—(CH₂)₂—,        and the like;

in another embodiment A comprises:

-   -   1) a) O; and 0, 1, 2, or 3 —CH₂— moieties; or        -   b) O; and 0 or 1 —CH₂— moieties and —CH═CH— or —C≡C—; and    -   2) Ar;    -   e.g., —O—Ar—, —Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —OAr—CH═CH—,        —O—Ar—C≡C—, —O—CH₂—Ar—, —O—CH₂—Ar—(CH₂)₂, —O—CH₂Ar—CH═CH—,        —O—CH₂Ar—C≡C—, and the like; or

in another embodiment A comprises:

-   -   1) a) S; and 0, 1, 2, or 3 —CH₂— moieties; or        -   b) S; and 0 or 1 —CH₂— moieties and —CH═CH— or —C≡C—; and    -   2) Ar;    -   e.g., —S—Ar—, —Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —SAr—CH═CH—,        —S—Ar—C≡C—, —S—CH₂—Ar—, —S—CH₂—Ar—(CH₂)₂, —S—CH₂Ar—CH═CH—,        —S—CH₂Ar—C≡C—, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O and 1 —CH₂—CH₂— may be replaced by —CH═CH—or —C≡C—.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O and 1 —CH₂—CH₂— may be replaced by —CH═CH— or—C≡C—.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O or 1 —CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O and 1 —CH₂—CH₂— may be replaced by —CH═CH— or—C≡C—.

Interarylene refers to an aryl ring or ring system, including aheteroaryl ring or ring system, which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene may be substituted or unsubstituted.Unsubstituted interarylene has no substituents other than the two partsof the molecule it connects. Substituted interarylene has substituentsin addition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. Substitutents of Ar must be stable, and each havefrom 0 to 4 carbon atoms, from 0 to 3 oxygen atoms, from 0 to 2 sulfuratoms, from 0 to 2 nitrogen atoms, from 0 to 3 fluorine atoms, from 0 to1 chlorine atoms, from 0 to 1 bromine atoms, from 0 to 1 iodine atoms,and from 0 to 10 hydrogen atoms. If a substituent is acidic or basic,the number of atoms indicated above refers to the neutral form of thesubstituent. For example, neutral forms include —CO₂H, not —CO₂ ⁻Na⁺; or—NH₃, not —NH₄ ⁺Cl⁻.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂-Ph-OCH₂—. In another embodiment, Ph (phenyl) is attached at the 1and 3 positions, otherwise known as m-interphenylene, such as when A hasthe structure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S or O; or Ais —(CH₂)₂-Ph- wherein one —CH₂— may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In one embodiment, Ar is thienyl.

In other embodiments, A has one of the following structures.

In another embodiment A is —CH₂OCH₂Ar—.

In another embodiment A is —CH₂SCH₂Ar—.

In another embodiment A is —(CH₂)₃Ar—.

In another embodiment A is —CH₂O(CH₂)₄—.

In another embodiment A is —CH₂S(CH₂)₄—.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)₃—.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-(methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl).

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

G is —H, —OH, —O-alkyl having from 1 to 6 carbon atoms, halo, C₁₋₆alkyl, —CF₃, —CN, or ═O.

In one embodiment, G is —H.

In another embodiment, G is —OH.

In another embodiment, G is —O-alkyl having from 1 to 6 carbon atoms. Inother words, G is -OMe, -OEt, -OiPr, etc., up to 6 carbon atoms.

In another embodiment, G is halo.

In another embodiment, G is C₁₋₆ alkyl.

In another embodiment, G is —CF₃.

In another embodiment, G is —CN.

In another embodiment, G is or ═O.

G′ is —H, —OH, —O-alkyl having from 1 to 6 carbon atoms, halo, C₁₋₆alkyl, —CF₃, —CN, or ═O.

In one embodiment, G′ is —H.

In another embodiment, G′ is —OH

In another embodiment, G′ is —O-alkyl having from 1 to 6 carbon atoms.In other words, G′ is —OMe, —OEt, —OiPr, etc., up to 6 carbon atoms.

In another embodiment, G′ is halo.

In another embodiment, G′ is C₁₋₆ alkyl.

In another embodiment, G′ is —CF₃.

In another embodiment, G′ is —CN.

In another embodiment, G′ is or ═O.

G and G′ are independent, meaning that the identity of one does notaffect the identity of the other. Thus, they could be the same, forexample, G and G′ could be —H. Or they could be different, for example,G might be —H and G′ might be ═O.

B is aryl.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like. Aryl also includes heteroaryl, which is anaromatic ring or ring system containing one or more O, N, or Sheteroatoms. Aryl may be substituted or unsubstituted, and unlessotherwise indicated, “aryl” or “heteroaryl” should be taken to mean“substituted or unsubstituted aryl” or “substituted or unsubstitutedheteroaryl.” Similarly, unless otherwise indicated, any specific arylring such as “phenyl,” “pyridinyl,” “thienyl,” “furyl,” etc., should betaken to mean “substituted or unsubstituted phenyl,” “substituted orunsubstituted pyridinyl,” “substituted or unsubstituted thienyl,”“substituted or unsubstituted furyl,” etc. The substituents of aryl forB must be stable, and may have from 0 to 12 carbon atoms, from 0 to 4oxygen atoms, from 0 to 2 sulfur atoms, from 0 to 3 nitrogen atoms, from0 to 3 fluorine atoms, from 0 to 2 chlorine atoms, from 0 to 2 bromineatoms, and from 0 to 1 iodine atoms. If a substituent is acidic orbasic, the number of atoms indicated above refers to the neutral form ofthe substituent. For example, neutral forms include —CO₂H, not —CO₂⁻Na⁺; or —NH₃, not —NH₄ ⁺Cl⁻.

In one embodiment, B is phenyl.

In another embodiment, B is pyridinyl.

In another embodiment, B is thienyl.

In another embodiment, B is furyl.

Examples of substituents may include the following, subject to theconstraints defined herein for that particular moiety or substituent:

-   -   A. Hydrocarbyl, including, but not limited to:        -   a. alkyl, such as:            -   linear alkyl, e.g. methyl, ethyl, n-propyl, n-butyl,                n-pentyl, n-hexyl, etc.,            -   branched alkyl, e.g. iso-propyl, t-butyl and other                branched butyl isomers, branched pentyl isomers, etc.,            -   cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,                cyclohexyl, etc.,            -   combinations of linear, branched, and/or cycloalkyl;        -   b. alkenyl, which is hydrocarbyl having 1 or more double            bonds, including linear, branched, or cycloalkenyl        -   c. alkynyl, which is hydrocarbyl having 1 or more triple            bonds, including linear, branched, or cycloalkynyl;        -   d. combinations of alkyl, alkenyl, and/or akynyl    -   B. alkyl-CN, such as —CH₂—CN, —(CH₂)₂—CN; —(CH₂)₃—CN, and the        like;    -   C. Hydroxy, —OH    -   D. hydroxyalkyl, i.e. alkyl-OH, such as hydroxymethyl,        hydroxyethyl, and the like;    -   E. ether substituents, including —O-alkyl, alkyl-O-alkyl, and        the like;    -   F. thioether substituents, including —S-alkyl, alkyl-S-alkyl,        and the like;    -   G. amine substituents, including —NH₂, —NH-alkyl,        —N-alkyl¹alkyl² (i.e., alkyl¹ and alkyl² are the same or        different, and both are attached to N), alkyl-NH₂,        alkyl-NH-alkyl, alkyl-N-alkyl¹alkyl², and the like;    -   H. aminoalkyl, meaning alkyl-amine, such as aminomethyl        (—CH₂-amine), aminoethyl, and the like;    -   I. ester substituents, including —CO₂-alkyl, —CO₂-phenyl, etc.;    -   J. other carbonyl substituents, including aldehydes; ketones,        such as acyl, including, acetyl, propionyl, and benzoyl        substituents;    -   K. fluorocarbons or hydrofluorocarbons such as —CF₃, CH₂CF₃,        etc.; and    -   L. other nitrogen containing substituents such as —CN and —NO₂,    -   M. other sulfur containing substitutents such as sulfide,        sulfonyl or sulfoxide;    -   N. aryl;    -   O. combinations of the above are also possible, subject to the        constraints defined;    -   P. Alternatively, a substituent may be —F, —Cl, —Br, or —I.

In one embodiment Y is CO₂R⁴.

In another embodiment G is hydrogen.

Another embodiment is a compound having a formula:

Another embodiment is a compound having a formula:

wherein each X¹ is independently —CH₂—, —O—, or —S—; and

-   X⁴ is —CH— or —N—.

Thus, since each X¹ is independent, X¹—X¹—X¹ could be —(CH₂)₃—,—O(CH₂)₂—, —S(CH₂)₂—, —(CH₂)₂O—, —(CH₂)₂S—, —CH₂OCH₂—, —CH₂SCH₂—, andthe like.

In one embodiment X₄ is —CH—.

In another embodiment X₄ is —N—.

Another embodiment is a compound having a formula:

Another embodiment is a compound having a formula:

In another embodiment G is hydrogen.

In another embodiment G′ is —H, —OH, —OCH₃, F, Cl, —CH₃, —CF₃, —CN, or═O.

In another embodiment G′ is —H.

In another embodiment G is —H, —OH, —OCH₃, F, Cl, —CH₃, —CF₃, —CN, or═O.

In another embodiment B is phenyl or pyridinyl.

In another embodiment B is phenyl.

In another embodiment B is phenyl with from 1 to 3 substituentsindependently selected from: —F, —Cl, —Br, —I, —OH, —NH₂, —NO₂, —OCH₃,—C₁₋₄ alkyl, —CF₃, —CN, —CHO, —CO₂H, and —CH₂OH.

In another embodiment B is dichlorophenyl.

Another embodiment is use of a compound disclosed herein in themanufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

Another embodiment is a method of treating glaucoma or ocularhypertension comprising administering a compound disclosed herein to amammal in need thereof.

A liquid composition comprising a compound disclosed herein and apharmaceutically acceptable excipient.

The structures depicted below are hypothetical examples of usefulcompounds.

Synthetic Methods

The compounds disclosed herein can be prepared by methods known in theart. For example, Schemes A-C illustrate an exemplary general methodthat might be employed.

The ω-chain (—CH₂CH₂—B) may be attached to the pyrrolidin-2-one core byemploying a method such as that shown in Scheme A. The coupling betweenB and C to obtain the coupled compound D could be carried out by anumber of methods known in the art. For example, the reaction might becatalyzed using a base such as sodium hydride. A different leaving groupthan Br might also be used for compound B.

The protected alcohol of compound D provides a good handle to prepare awide range of α-chains. For example, it could be oxidized to an aldehyde(E) and coupled to X-A′-Y via a Wittig-type coupling, where X is aphosphonium species. This may be hydrogenated to give a saturated C—Cbond, or the unsaturated bond may be retained. Compound D could also bedeprotected (F) or converted to SH (G) and coupled to X-A′-Y via anuceophilic substitution, where X is a leaving group.

Substituents on the pyrrolidin-2-one core may be added by employingmethods described in U.S. patent application Ser. No. 11/836,655, filedAug. 9, 2007, on Compound H.

EXAMPLE 1(R)-5-(((1-(3,5-dichlorophenethyl)-5-oxopyrrolidin-2-yl)methoxy)methyl)thiophene-2-carboxylicacid (7)

Step 1. Preparation of Bromide 2

Bromine (0.80 mL, 15.5 mmol) was added to a solution oftriphenylphosphine (4.12 g, 15.7 mmol) and imidazole (1.07 g, 15.7 mmol)in CH₂Cl₂ (52 mL) at 0° C. and the mixture was allowed to warm to roomtemperature. A solution of 2-(3,5-dichlorophenyl)ethanol (1, 2.5 g, 13.1mmol) in CH₂Cl₂ (13 mL) was added via cannula. After 30 min at roomtemperature, the mixture was filtered through celite, washing withexcess CH₂Cl₂. The filtrate was concentrated in vacuo. The crude residuewas purified by chromatography on 120 g silica (hexanes →20%EtOAc/hexanes, gradient) to afford 3.13 g (94%) of bromide 2.

Step 2. Alkylation of 3 with 2 to Give 4

Sodium hydride (80 mg of a 60% dispersion in oil, 2.0 mmol) was added toa solution of 3 (115 mg, 0.50 mmol) in DMF (4 mL). After 45 min at roomtemperature, a solution of bromide 2 (255 mg, 1.0 mmol) in DMF (1 mL)was added via cannula. The mixture was heated at 50° C. for 18 h, thencooled to room temperature and quenched with saturated aqueous NH₄Cl (20mL). The mixture was extracted with EtOAc (125 mL). The organic phasewas washed with water (2×50 mL) and brine (50 mL), then dried (Na₂SO₄),filtered and concentrated in vacuo. The crude residue was purified bychromatography on 12 g silica gel (hexanes →EtOAc, gradient) to afford39 mg (27%) of alcohol 4.

Step 3. Alkylation of 4 with 5 to Give 6

Sodium hydride (21 mg of a 60% dispersion in oil, 0.53 mmol) was addedto a solution of 4 (100 mg, 0.35 mmol) in DMF (0.43 mL) at 0° C. and themixture was allowed to warm to room temperature. After 30 min at roomtemperature, the mixture was cooled to −40° C. and a solution of bromide5 (see U.S. Provisional Patent Application 60/804,680, filed Jun. 14,2006, 70 mg, 0.30 mmol) in DMF (0.43 mL) was added via cannula. After 10min at −40° C., the reaction was partitioned between water (10 mL) andCH₂Cl₂ (20 mL). The phases were separated and the aqueous phase wasextracted with additional CH₂Cl₂ (2×10 mL). The combined organic phasewas dried (MgSO₄), filtered and concentrated in vacuo. The crude residuewas purified by chromatography on silica gel (hexanes →EtOAc, gradient)to afford 84 mg (64%) of 6.

Step 4. Saponification of 6 to Give 7

Aqueous 1.0 N lithium hydroxide (0.36 mL, 0.36 mmol) was added to asolution of ester 6 (40 mg, 0.090 mmol) in THF (0.9 mL). The solutionwas heated at 40° C. for 18 h, then cooled to room temperature. Themixture was quenched with 10% aqueous HCl (10 mL) and extracted withEtOAc (2×20 mL). The combined organic phase was washed with brine (10mL), dried (MgSO₄), filtered and concentrated in vacuo. Purification ofthe crude residue by chromatography on 4 g silica gel (CH₂Cl₂→10%MeOH/CH₂Cl₂, gradient) afforded 11 mg (28%) of the title compound.

EXAMPLE 2(S)-5-(3-(1-(3,5-dichlorophenethyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylicacid (12)

Step 1. Oxidation of 4 to Give 8

DMSO (65 μL, 0.92 mmol) was added to a solution of oxalyl chloride (220μL of a 2.0 M solution in CH₂Cl₂, 0.44 mmol) and CH₂Cl₂ (3.1 mL) at −78°C. After 15 min, a solution of alcohol 4 (100 mg, 0.35 mmol) in CH₂Cl₂(1.0 mL) was added via cannula. After 15 min, triethylamine (412 μL,2.96 mmol) was added and the reaction mixture was allowed to warm toroom temperature. After 1 h at room temperature the mixture waspartitioned between CH₂Cl₂ (25 mL) and saturated aqueous NaHCO₃ (25 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (2×30 mL). The combined organic phase was dried (Na₂SO₄),filtered and concentrated in vacuo to afford 100 mg (quant.) of crudealdehyde 8 which was used without further purification.

Step 2. Wittig Reaction of 8 with 9, Followed by Esterification to Give10

A solution of sodium bis(trimethylsilyl)amide (0.7 mL of a 1.0 Msolution in THF, 0.70 mmol) was added to a solution of phosphonium salt9 (see U.S. Prov PA No. 60/894,267, 173 mg, 0.35 mmol) in1-methyl-2-pyrrolidinone (NMP, 0.5 mL) at 0° C. After stirringvigorously for 30 min at 0° C., the mixture was cooled to −20° C. and asolution of aldehyde 8 (50 mg, 0.17 mmol) in THF (0.4 mL) was added bysyringe. After 30 min at −20° C. the mixture was allowed to warm to 0°C. After 1 h at 0° C., the reaction was quenched with saturated aqueousNH₄Cl (10 mL) and diluted with CH₂Cl₂ (25 mL). The resulting emulsionwas filtered through celite, washing with CH₂Cl₂. The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×75 mL). Thecombined organic phase was dried (Na₂SO₄), filtered and concentrated invacuo. The crude material was dissolved in THF (0.87 mL) and treateddropwise with a solution of (trimethylsilyl)diazomethane (0.43 mL of a2.0 M solution in Et₂O, 0.86 mmol). After 30 min at room temperature,the reaction mixture was concentrated in vacuo.

Purification of the crude residue by chromatography on 12 g silica gel(CH₂Cl₂→15% MeOH/CH₂Cl₂, gradient) gave a poor separation of desiredproduct and impurities. Fractions containing the desired product wereconcentrated in vacuo and purified by chromatography on 12 g silica gel(50% EtOAc/hexanes→EtOAc, gradient) to afford 14 mg (18%) of ester 10 asa mixture of olefin isomers.

Step 3. Hydrogenation of 10 to Give 11

Palladium on carbon (10 wt. %, 6.8 mg) was added to a solution of alkene10 (14 mg, 0.032 mmol) in MeOH (0.7 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (5×) and themixture was stirred under a balloon of hydrogen. After 18 h, thereaction was filtered through celite, washing with excess MeOH. Thefiltrate was concentrated in vacuo. Purification of the crude residue on4 g silica gel (35% EtOAc/hexanes→80% EtOAc/hexanes, gradient) afforded3 mg (21%) of 11.

Step 4. Saponification of 11 to Give 12

Aqueous 1.0 N lithium hydroxide (0.05 mL, 0.05 mmol) was added to asolution of ester 11 (2 mg, 0.0045 mmol) in THF (0.1 mL). After 18 h at30° C., the mixture was cooled and the volatiles were removed under asstream of nitrogen. The residue was diluted with water (0.2 mL) andacidified with 1 N aqueous HCl (0.5 mL). The mixture was extracted withEtOAc (3×2 mL). The combined extracts were washed with brine (1 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Purification of thecrude residue by chromatography on 4 g silica gel (CH₂Cl₂→20%MeOH/CH₂Cl₂, gradient) afforded 1.3 mg (67%) of the title compound.

In vitro Testing

U.S. patent application Ser. No. 11/553,143, filed on Oct. 26, 2006,incorporated by reference herein, describes the methods used to obtainthe in vitro data in the table below.

TABLE 1 EP2 data EP4 data flipr cAMP flipr Other Receptors (EC50 in nM)Structure EC50 EC50 KI EC50 KI hFP hEP1 hEP3A hTP hIP hDP

>10000 4 159 >10000 7990 NA NA NA NA NA NA

8412 2.2 24 NT >10000 NA NA NA NA NA 6225

1. A compound of the formula:

wherein Y has from 0 to 14 carbon atoms and is: a carboxylic acid group,or an amide or ester thereof; hydroxymethyl or an ether thereof; or atetrazolyl functional group; A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced by S or O;or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene, the sum ofm and o is 1, 2, 3, or 4, and wherein 1 —CH₂— may be replaced by S or O,and 1 —CH₂—CH₂— may be replaced by —CH═CH— or —C≡C—; G and G′ areindependently —H, —OH, —O-alkyl having from 1 to 6 carbon atoms, halo,C₁₋₆ alkyl, —CF₃, —CN, or ═O; and B is aryl.
 2. The compound of claim 1wherein Y is —CO₂R⁴, —CONR⁵R⁶, —CON(CH₂CH₂OH)₂, —CONH(CH₂CH₂OH), —CH₂OH,

wherein R⁴, R⁵ and R⁶ are independently H, C₁-C₆ alkyl, C₁₋₆hydroxyalkyl, unsubstituted phenyl, or unsubstituted biphenyl.
 3. Thecompound of claim 2 wherein Y is CO₂R⁴.
 4. The compound of claim 3wherein G is hydrogen.
 5. The compound of claim 4 of the formula:


6. The compound of claim 4 of the formula:


7. The compound of claim 1 of the formula:

wherein each X¹ is independently —CH₂—, —O—, or —S—; and X⁴ is —CH— or—N—.
 8. The compound of claim 7 of the formula


9. The compound of claim 7 of the formula


10. The compound of claim 1 wherein G is hydrogen.
 11. The compound ofclaim 1 wherein G′ is —H, —OH, —OCH₃, F, Cl, —CH₃, —CF₃, —CN, or ═O. 12.The compound of claim 11 wherein G′ is —H.
 13. The compound of claim 11wherein G is —H, —OH, —OCH₃, F, Cl, —CH₃, —CF₃, —CN, or ═O.
 14. Thecompound of claim 1 wherein B is phenyl or pyridinyl.
 15. The compoundof claim 14 wherein B is phenyl.
 16. The compound of claim 15 wherein Bis phenyl with from 1 to 3 substituents independently selected from: —F,—Cl, —Br, —I, —OH, —NH₂, —NO₂, —OCH₃, —C₁₋₄ alkyl, —CF₃, —CN, —CHO,—CO₂H, and —CH₂OH.
 17. The compound of claim 14 wherein B isdichlorophenyl.
 18. A method of treatment for glaucoma or ocularhypertension comprising administering a compound according to claim 1 toa mammal in need thereof, wherein treatment is mitigation.
 19. A liquidcomposition comprising a compound according to claim 1 and apharmaceutically acceptable excipient.